The expression of vascular endothelial growth factor (VEGF)-A/ VAGF receptors (VEGFRs) signaling plays a pivotal role in the tumor angiogenesis and the development of the immunosuppressive tumor microenvironment in glioblastomas. We have previously conducted exploratory clinical studies investigating VEGFRs peptide vaccination with and without multiple glioma oncoantigens in patients with recurrent high-grade gliomas. Recently, an exploratory clinical investigation of VEGFRs peptide vaccination was conducted in patients with progressive neurofibromatosis type 2. Those studies suggested that cytotoxic T lymphocytes (CTLs) induced by the vaccination can directly kill a wide variety of cells associated with tumor growth, including tumor vessels, tumor cells, and immunosuppressive cells expressing VEGFR1 and/or 2. In the present study, synergistic activity of the combination of VEGFRs peptide vaccination with chemotherapy was evaluated. We performed the first clinical trial to assess VEGFR1 and 2 vaccination along with temozolomide (TMZ) -based chemoradiotherapy for the patients with primary glioblastomas. Furthermore, histopathological changes after the vaccination were evaluated using paired pre- and post- vaccination specimens. The disappearance of radiographically enhanced lesion was observed in 2 patients after the vaccination, including one in which the methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter was not observed. The histopathological findings of pre- and post-vaccination specimens demonstrated that tumor vessels showed negative or slight VEGFRs expressions after the vaccination and most endothelial cells were covered with PDGFR-β-positive pericytes. Notably, CTLs induced by VEGFRs peptide vaccination attacked not only tumor vessels but also tumor cells and regulatory T cells expressing VEGFRs even in recurrent tumors. VEGFR1 and 2 vaccination may have a preliminary synergistic effect when administered with TMZ. The limitation of the present study was the paucity of the number of the samples. Further studies involving more patients are warranted to confirm the findings of this study. This study was registered as UMIN000013381 (University Hospital Medical Information Network-Clinical Trial Registry: UMIN-CTR) on 5 March, 2014 and with the Japan Registry of Clinical Trials (jRCT) as jRCTs031180170 on 1 March, 2019.

中文翻译：

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原发性胶质母细胞瘤患者中VEGF受体肽疫苗的临床和组织病理学分析-病例系列。

血管内皮生长因子（VEGF）-A / VAGF受体（VEGFRs）信号的表达在胶质母细胞瘤的肿瘤血管生成和免疫抑制肿瘤微环境的发展中起着关键作用。我们先前已经进行了探索性临床研究，研究了在复发性高级别神经胶质瘤患者中是否伴有多种胶质瘤癌抗原的VEGFRs肽疫苗接种。最近，对2型进行性神经纤维瘤病患者进行了VEGFRs肽疫苗接种的探索性临床研究。这些研究表明，疫苗诱导的细胞毒性T淋巴细胞（CTL）可以直接杀死与肿瘤生长相关的多种细胞，包括肿瘤血管，肿瘤细胞和表达VEGFR1和/或2的免疫抑制细胞。在本研究中，评价了VEGFRs肽疫苗接种与化学疗法联合的协同活性。我们进行了第一项临床试验，以评估针对原发性胶质母细胞瘤患者的VEGFR1和2疫苗接种以及基于替莫唑胺（TMZ）的放化疗。此外，使用配对的疫苗接种前后样本评估了疫苗接种后的组织病理学变化。接种疫苗后的2例患者出现了影像学上增强的病变的消失，其中1例未观察到O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）启动子的甲基化。接种前和接种后标本的组织病理学发现表明，接种疫苗后肿瘤血管显示阴性或轻微的VEGFRs表达，大多数内皮细胞被PDGFR-β阳性周细胞覆盖。值得注意的是，由VEGFRs疫苗接种诱导的CTL不仅攻击肿瘤血管，而且甚至在复发性肿瘤中也攻击表达VEGFRs的肿瘤细胞和调节性T细胞。与TMZ一起使用时，VEGFR1和2疫苗接种可能具有初步的协同作用。本研究的局限性在于样本数量的匮乏。有必要让更多患者参加进一步的研究，以证实这项研究的结果。该研究于3月5日注册为UMIN000013381（大学医院医疗信息网络-临床试验注册中心：UMIN-CTR），